Page last updated: 2024-10-24

ubiquitin-dependent protein catabolic process

Definition

Target type: biologicalprocess

The chemical reactions and pathways resulting in the breakdown of a protein or peptide by hydrolysis of its peptide bonds, initiated by the covalent attachment of a ubiquitin group, or multiple ubiquitin groups, to the protein. [GOC:go_curators]

Ubiquitin-dependent protein catabolic process is a fundamental cellular process responsible for the selective degradation of proteins. It plays a crucial role in maintaining cellular homeostasis by removing misfolded or damaged proteins, regulating protein levels, and controlling signaling pathways. This process involves a cascade of enzymatic reactions that tag target proteins with ubiquitin, a small protein, leading to their recognition and degradation by the proteasome, a large protein complex.

The ubiquitin-dependent protein catabolic process begins with the activation of ubiquitin by the E1 enzyme, an ubiquitin-activating enzyme. This process involves the ATP-dependent binding of ubiquitin to E1, forming a high-energy thioester bond. The activated ubiquitin is then transferred to an E2 enzyme, an ubiquitin-conjugating enzyme. The E2 enzyme, in turn, transfers the ubiquitin to the target protein, which is facilitated by an E3 enzyme, an ubiquitin ligase.

E3 ligases are highly specific and recognize specific target proteins based on their degradation signal, typically a short amino acid sequence. The E3 ligase brings the target protein and the ubiquitin-charged E2 enzyme together, allowing the transfer of ubiquitin to the target protein. This process is repeated multiple times, resulting in the formation of a polyubiquitin chain on the target protein.

Polyubiquitin chains act as a signal for the proteasome, a barrel-shaped protein complex responsible for protein degradation. The proteasome recognizes the polyubiquitin chain and unfolds the target protein, feeding it into the proteasome's central chamber, where it is degraded into small peptides. The ubiquitin chains are then removed and recycled.

The ubiquitin-dependent protein catabolic process is highly regulated and plays a critical role in various cellular functions, including:

* **Protein quality control:** Removal of misfolded or damaged proteins prevents their accumulation, which can lead to cellular dysfunction.
* **Cellular signaling:** Degradation of signaling proteins can regulate the duration and intensity of signaling pathways.
* **Cell cycle control:** Degradation of key cell cycle regulators ensures proper progression through the cell cycle.
* **Immune response:** Degradation of antigens and other molecules involved in the immune response is essential for immune regulation.
* **Developmental processes:** Degradation of specific proteins is crucial for proper development and differentiation.

Dysregulation of the ubiquitin-dependent protein catabolic process can lead to various diseases, including cancer, neurodegenerative disorders, and inflammatory diseases. Understanding the intricacies of this process is crucial for developing new therapies to treat these diseases.'
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Proteins (21)

ProteinDefinitionTaxonomy
26S proteasome non-ATPase regulatory subunit 13A 26S proteasome non-ATPase regulatory subunit 13 that is encoded in the genome of human. [PRO:DNx]Homo sapiens (human)
Ubiquitin-like modifier-activating enzyme 1A ubiquitin-like modifier-activating enzyme 1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P22314]Homo sapiens (human)
Elongin-CAn elongin-C that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q15369]Homo sapiens (human)
NEDD8-activating enzyme E1 regulatory subunitA NEDD8-activating enzyme E1 regulatory subunit that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q13564]Homo sapiens (human)
26S proteasome non-ATPase regulatory subunit 3A 26S proteasome non-ATPase regulatory subunit 3 that is encoded in the genome of human. [PRO:DNx]Homo sapiens (human)
Ubiquitin carboxyl-terminal hydrolase isozyme L5A ubiquitin carboxyl-terminal hydrolase isozyme L5 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9Y5K5]Homo sapiens (human)
Methylosome protein 50A methylosome protein WDR77 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9BQA1]Homo sapiens (human)
E3 ubiquitin-protein ligase UHRF1An E3 ubiquitin-protein ligase UHRF1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q96T88]Homo sapiens (human)
Ubiquitin carboxyl-terminal hydrolase BAP1A ubiquitin carboxyl-terminal hydrolase BAP1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q92560]Homo sapiens (human)
DNA damage-binding protein 1A DNA damage-binding protein 1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q16531]Homo sapiens (human)
NEDD8A NEDD8 protein that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q15843]Homo sapiens (human)
Kelch-like ECH-associated protein 1A kelch-like ECH-associated protein 1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q14145]Homo sapiens (human)
E3 ubiquitin-protein ligase Mdm2An E3 ubiquitin-protein ligase Mdm2 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q00987]Homo sapiens (human)
E3 ubiquitin-protein ligase Mdm2An E3 ubiquitin-protein ligase Mdm2 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q00987]Homo sapiens (human)
Transitional endoplasmic reticulum ATPaseA transitional endoplasmic reticulum ATPase that is encoded in the genome of human. [PRO:DNx, UniProtKB:P55072]Homo sapiens (human)
26S proteasome regulatory subunit 7A 26S proteasome regulatory subunit 7 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P35998]Homo sapiens (human)
Transcription initiation factor TFIID subunit 1A transcription initiation factor TFIID subunit 1 that is encoded in the genome of human. [PRO:DNx]Homo sapiens (human)
Ubiquitin carboxyl-terminal hydrolase isozyme L3A ubiquitin carboxyl-terminal hydrolase isozyme L3 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P15374]Homo sapiens (human)
26S proteasome non-ATPase regulatory subunit 14A 26S proteasome non-ATPase regulatory subunit 14 that is encoded in the genome of human. [PRO:DNx, UniProtKB:O00487]Homo sapiens (human)
26S proteasome non-ATPase regulatory subunit 11A 26S proteasome non-ATPase regulatory subunit 11 that is encoded in the genome of human. [PRO:WCB, UniProtKB:O00231]Homo sapiens (human)
Ubiquitin-like modifier-activating enzyme 6A ubiquitin-like modifier-activating enzyme 6 that is encoded in the genome of human. [PRO:DNx, UniProtKB:A0AVT1]Homo sapiens (human)

Compounds (77)

CompoundDefinitionClassesRoles
3-phenylpropionic acid3-phenylpropionic acid : A monocarboxylic acid that is propionic acid substituted at position 3 by a phenyl group.

3-phenylpropionic acid: RN given refers to parent cpd
benzenes;
monocarboxylic acid
antifungal agent;
human metabolite;
plant metabolite
catecholcatecholsallelochemical;
genotoxin;
plant metabolite
oxyquinolineOxyquinoline: An antiseptic with mild fungistatic, bacteriostatic, anthelmintic, and amebicidal action. It is also used as a reagent and metal chelator, as a carrier for radio-indium for diagnostic purposes, and its halogenated derivatives are used in addition as topical anti-infective agents and oral antiamebics.

quinolin-8-ol : A monohydroxyquinoline that is quinoline substituted by a hydroxy group at position 8. Its fungicidal properties are used for the control of grey mould on vines and tomatoes.
monohydroxyquinolineantibacterial agent;
antifungal agrochemical;
antiseptic drug;
iron chelator
candesartan cilexetilcandesartan cilexetil: a prodrug which is metabolized to an active form candesartan to exert its biological effectsbiphenyls
clotrimazoleconazole antifungal drug;
imidazole antifungal drug;
imidazoles;
monochlorobenzenes
antiinfective agent;
environmental contaminant;
xenobiotic
gossypolGossypol: A dimeric sesquiterpene found in cottonseed (GOSSYPIUM). The (-) isomer is active as a male contraceptive (CONTRACEPTIVE AGENTS, MALE) whereas toxic symptoms are associated with the (+) isomer.
vitamin k 3Vitamin K 3: A synthetic naphthoquinone without the isoprenoid side chain and biological activity, but can be converted to active vitamin K2, menaquinone, after alkylation in vivo.1,4-naphthoquinones;
vitamin K
angiogenesis inhibitor;
antineoplastic agent;
EC 3.4.22.69 (SARS coronavirus main proteinase) inhibitor;
human urinary metabolite;
nutraceutical
mitoxantronemitoxantrone : A dihydroxyanthraquinone that is 1,4-dihydroxy-9,10-anthraquinone which is substituted by 6-hydroxy-1,4-diazahexyl groups at positions 5 and 8.

Mitoxantrone: An anthracenedione-derived antineoplastic agent.
dihydroxyanthraquinoneanalgesic;
antineoplastic agent
quinone1,4-benzoquinone : The simplest member of the class of 1,4-benzoquinones, obtained by the formal oxidation of hydroquinone to the corresponding diketone. It is a metabolite of benzene.

benzoquinone : The simplest members of the class of benzoquinones, consisting of cyclohexadiene which is substituted by two oxo groups.

quinone : Compounds having a fully conjugated cyclic dione structure, such as that of benzoquinones, derived from aromatic compounds by conversion of an even number of -CH= groups into -C(=O)- groups with any necessary rearrangement of double bonds (polycyclic and heterocyclic analogues are included).
1,4-benzoquinonescofactor;
human xenobiotic metabolite;
mouse metabolite
vorinostatvorinostat : A dicarboxylic acid diamide comprising suberic (octanedioic) acid coupled to aniline and hydroxylamine. A histone deacetylase inhibitor, it is marketed under the name Zolinza for the treatment of cutaneous T cell lymphoma (CTCL).

Vorinostat: A hydroxamic acid and anilide derivative that acts as a HISTONE DEACETYLASE inhibitor. It is used in the treatment of CUTANEOUS T-CELL LYMPHOMA and SEZARY SYNDROME.
dicarboxylic acid diamide;
hydroxamic acid
antineoplastic agent;
apoptosis inducer;
EC 3.5.1.98 (histone deacetylase) inhibitor
sulforaphanesulforaphane : An isothiocyanate having a 4-(methylsulfinyl)butyl group attached to the nitrogen.

sulforaphane: from Cardaria draba L.
isothiocyanate;
sulfoxide
antineoplastic agent;
antioxidant;
EC 3.5.1.98 (histone deacetylase) inhibitor;
plant metabolite
thalidomide2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione : A dicarboximide that is isoindole-1,3(2H)-dione in which the hydrogen attached to the nitrogen is substituted by a 2,6-dioxopiperidin-3-yl group.

thalidomide : A racemate comprising equimolar amounts of R- and S-thalidomide.

Thalidomide: A piperidinyl isoindole originally introduced as a non-barbiturate hypnotic, but withdrawn from the market due to teratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppressive and anti-angiogenic activity. It inhibits release of TUMOR NECROSIS FACTOR-ALPHA from monocytes, and modulates other cytokine action.
phthalimides;
piperidones
tiaprofenic acidtiaprofenic acid : An aromatic ketone that is thiophene substituted at C-2 by benzoyl and at C-4 by a 1-carboxyethyl group.

tiaprofenic acid: RN given refers to parent cpd; structure
aromatic ketone;
monocarboxylic acid;
thiophenes
drug allergen;
non-steroidal anti-inflammatory drug
apomorphineApomorphine: A derivative of morphine that is a dopamine D2 agonist. It is a powerful emetic and has been used for that effect in acute poisoning. It has also been used in the diagnosis and treatment of parkinsonism, but its adverse effects limit its use.aporphine alkaloidalpha-adrenergic drug;
antidyskinesia agent;
antiparkinson drug;
dopamine agonist;
emetic;
serotonergic drug
cytarabinebeta-D-arabinoside;
monosaccharide derivative;
pyrimidine nucleoside
antimetabolite;
antineoplastic agent;
antiviral agent;
immunosuppressive agent
1-naphthylamine1-naphthylamine : A naphthylamine that is naphthalene substituted by an amino group at position 1.

1-Naphthylamine: A suspected industrial carcinogen (and listed as such by OSHA). Its N-hydroxy metabolite is strongly carcinogenic and mutagenic.

naphthylamine : A primary arylamine that is naphthalene substituted by an amino group at unspecified position.
naphthylaminehuman xenobiotic metabolite
iberinisothiocyanate;
sulfoxide
apoptosis inducer;
plant metabolite;
quorum sensing inhibitor
8-aminoquinoline
8-methylquinolinemethylquinoline
s-adenosylmethionineacylcarnitine: structure in first source

S-adenosyl-L-methioninate : A sulfonium betaine that is a conjugate base of S-adenosyl-L-methionine obtained by the deprotonation of the carboxy group.
sulfonium betainehuman metabolite
3-morpholinopropylamine3-morpholinopropylamine : A member of the class of morpholines that is morpholine substituted by a 3-aminopropyl group a the N atom.morpholines;
primary amino compound
2,4'-bisphenol f2,4'-bisphenol F: contact allergen; structure given in first source
hei 712organofluorine compound;
quinolone
8-mercaptoquinoline8-mercaptoquinoline: structure given in first source
celastrolmonocarboxylic acid;
pentacyclic triterpenoid
anti-inflammatory drug;
antineoplastic agent;
antioxidant;
EC 5.99.1.3 [DNA topoisomerase (ATP-hydrolysing)] inhibitor;
Hsp90 inhibitor;
metabolite
pomalidomide3-aminophthalimidoglutarimide: structure in first sourcearomatic amine;
dicarboximide;
isoindoles;
piperidones
angiogenesis inhibitor;
antineoplastic agent;
immunomodulator
perifosineammonium betaine;
phospholipid
EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor
2-(5-Chlorobenzo[b]thiophen-3-yl)acetic acid1-benzothiophenes
alyssinsulfoxide
lenalidomidearomatic amine;
dicarboximide;
isoindoles;
piperidones
angiogenesis inhibitor;
antineoplastic agent;
immunomodulator
nutlin 3stilbenoid
bortezomibamino acid amide;
L-phenylalanine derivative;
pyrazines
antineoplastic agent;
antiprotozoal drug;
protease inhibitor;
proteasome inhibitor
s-adenosylhomocysteineS-adenosyl-L-homocysteine : An organic sulfide that is the S-adenosyl derivative of L-homocysteine.

S-Adenosylhomocysteine: 5'-S-(3-Amino-3-carboxypropyl)-5'-thioadenosine. Formed from S-adenosylmethionine after transmethylation reactions.
adenosines;
amino acid zwitterion;
homocysteine derivative;
homocysteines;
organic sulfide
cofactor;
EC 2.1.1.72 [site-specific DNA-methyltransferase (adenine-specific)] inhibitor;
EC 2.1.1.79 (cyclopropane-fatty-acyl-phospholipid synthase) inhibitor;
epitope;
fundamental metabolite
5'-methylthioadenosine5'-methylthioadenosine: structure

5'-S-methyl-5'-thioadenosine : Adenosine with the hydroxy group at C-5' substituted with a methylthio (methylsulfanyl) group.
thioadenosinealgal metabolite;
Escherichia coli metabolite;
human metabolite;
mouse metabolite;
Saccharomyces cerevisiae metabolite
dimethyl fumaratediester;
enoate ester;
methyl ester
antipsoriatic;
immunomodulator
Methylenedioxycinnamic acidhydroxycinnamic acid
5-(1,3-benzodioxol-5-yl)-N-(2-furanylmethyl)-7-(trifluoromethyl)-2-pyrazolo[1,5-a]pyrimidinecarboxamidepyrazolopyrimidine
3,4-methylenedioxy-beta-nitrostyrene3,4-methylenedioxy-beta-nitrostyrene: tyrosine kinase inhibitor that prevents platelet glycoprotein IIb/IIIa activation; structure in first source
4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenolsubstituted aniline
umi-77UMI-77: an Mcl-1 inhibitor; structure in first source
N-[2-(4-acetyl-1-piperazinyl)phenyl]-2-(5-methyl-2-propan-2-ylphenoxy)acetamidepiperazines
4,5,6,7-tetrachloroindan-1,3-dione4,5,6,7-tetrachloroindan-1,3-dione: inhibits ubiquitin C-terminal hydrolase L1
9-deoxy-delta-9-prostaglandin d29-deoxy-delta-9-prostaglandin D2: has potent antineoplastic & weak smooth muscle contracting activities; structure given in first source

prostaglandin J2 : A member of the class of prostaglandins J that consists of prosta-5,9,13-trien-1-oic acid substituted by an oxo group at position 11 and a hydroxy group at position 15 (the 5Z,13E,15S stereoisomer).
prostaglandins Jhuman metabolite
nutlin 2
acetyl isogambogic acidacetyl isogambogic acid: structure in first source
6-methylsulfinylhexyl isothiocyanate6-(Methylsulfinyl)hexyl isothiocyanate: showed a dose-dependent inhibition of LPS-induced nitric oxide (NO), iNOS mRNA and protein.sulfoxide
nutlin 1nutlin 1: an MDM2 antagonist; structure in first source
panepophenanthrinpanepophenanthrin: from a mushroom strain, an inhibitor of the ubiquitin-activating enzyme; structure in first source
bi 2536
nutlin-3anutlin 3: an MDM2 antagonist; structure in first sourcestilbenoid
MI-63MI-63 : An azaspiro compound resulting from the formal fusion of position 3 of 6-chloro-oxindole with position 3 of (2R,3SS5S)-3-(3-chloro-2-fluorophenyl)-5-(2,2-dimethylpropyl)-N-[2-(morpholin-4-yl)ethyl]pyrrolidine-2-carboxamide. It is a potent inhibitor of the MDM2-p53 interaction.azaspiro compound;
monochlorobenzenes;
monofluorobenzenes;
morpholines;
oxindoles;
pyrrolidines;
secondary carboxamide
apoptosis inducer
carfilzomibepoxide;
morpholines;
tetrapeptide
antineoplastic agent;
proteasome inhibitor
pevonedistatpevonedistat : A pyrrolopyrimidine that is 7H-pyrrolo[2,3-d]pyrimidine which is substituted by a (1S)-2,3-dihydro-1H-inden-1-ylnitrilo group at position 4 and by a (1S,3S,4S)-3-hydroxy-4-[(sulfamoyloxy)methyl]cyclopentyl group at position 7. It is a potent and selective NEDD8-activating enzyme inhibitor with an IC50 of 4.7 nM, and currently under clinical investigation for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes.

pevonedistat: a potent and selective inhibitor of NAE (NEDD8-activating enzyme)
cyclopentanols;
indanes;
pyrrolopyrimidine;
secondary amino compound;
sulfamidate
antineoplastic agent;
apoptosis inducer
nutlin-3bNutlin;
piperazinone
anticoronaviral agent
largazolelargazole: an antiproliferative agent from Symploca; structure in first source
belactosin abelactosin A: isolated from Streptomyces; structure in first source
pb 12
(3R)-4-[2-(1H-indol-4-yl)-6-(1-methylsulfonylcyclopropyl)-4-pyrimidinyl]-3-methylmorpholineindoles
jq1 compoundcarboxylic ester;
organochlorine compound;
tert-butyl ester;
thienotriazolodiazepine
angiogenesis inhibitor;
anti-inflammatory agent;
antineoplastic agent;
apoptosis inducer;
bromodomain-containing protein 4 inhibitor;
cardioprotective agent;
ferroptosis inducer
(5-bromo-3-pyridinyl)-[4-(1-pyrrolidinyl)-1-piperidinyl]methanonearomatic carboxylic acid;
pyridinemonocarboxylic acid
ML240ML240 : A member of the class of quinazolines that is quinazoline which is substituted at positions 2, 5 and 8 by 2-amino-1H-benzimidazol-1-yl, benzylnitrilo and methoxy groups, respectively. It is a ATP-competetive inhibitor of AAA ATPase p97, also known as valosin-containing protein (VCP).aromatic amine;
aromatic ether;
benzimidazoles;
primary amino compound;
quinazolines;
secondary amino compound
antineoplastic agent
spautin-1
ldn 57444LDN 57444: inhibitor of ubiquitin C-terminal hydrolase-L1; structure in first source
i-bet726
nvp-cgm097NVP-CGM097: an MDM2 and HDM2 inhibitor; structure in first source
rg7388RG7388: structure in first source
sar405838SAR405838: an inhibitor of the interaction of MDM2 and p53; has antineoplastic activity; structure in first source
(1S,2R)-2-[[(1S)-1-[(1,3-dioxo-2-isoindolyl)methyl]-3,4-dihydro-1H-isoquinolin-2-yl]-oxomethyl]-1-cyclohexanecarboxylic acidLH601A: inhibits the interaction between KEAP1 and NRF2; structure in first sourcephthalimides
epz004777N-glycosyl compound
entecavirbenzamides;
N-acylpiperidine
rg7112
amg 232
nk 252NK 252: potentiates the action of antitumor drugs against drug-sensitive tumors; structure given in first source
gsk3235025GSK3235025: an inhibitor of protein arginine methyltransferase-5 (PRMT5); structure in first source
MZ1organic molecular entity
ganciclovir2-aminopurines;
oxopurine
antiinfective agent;
antiviral drug
4-[[2-[(6-methyl-4-oxo-1H-pyrimidin-2-yl)thio]-1-oxoethyl]amino]benzoic acid ethyl esteramidobenzoic acid